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Metformin Attenuated the Autoimmune Disease of the Central Nervous System in Animal Models of Multiple Sclerosis¹

Narender Nath^*, Musfiquidin Khan^*, Manjeet K. Paintlia^*, Md Nasrul Hoda^* and Shailendra Giri^2,

^* Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425; and Department of Experimental Pathology, Mayo Clinic, Rochester, MN 55905

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS. Metformin is the most widely used drug for diabetes and mediates its action via activating AMP-activated protein kinase (AMPK). We provide evidence that metformin attenuates the induction of EAE by restricting the infiltration of mononuclear cells into the CNS, down-regulating the expression of proinflammatory cytokines (IFN-, TNF-, IL-6, IL-17, and inducible NO synthase (iNOS)), cell adhesion molecules, matrix metalloproteinase 9, and chemokine (RANTES). Furthermore, the AMPK activity and lipids alterations (total phospholipids and in free fatty acids) were restored by metformin treatment in the CNS of treated EAE animals, suggesting the possible involvement of AMPK. Metformin activated AMPK in macrophages and thereby inhibited biosynthesis of phospholipids as well as neutral lipids and also down-regulated the expression of endotoxin (LPS)-induced proinflammatory cytokines and their mediators (iNOS and cyclooxygenase 2). It also attenuated IFN- and IL-17-induced iNOS and cyclooxygenase 2 expression in RAW267.4 cells, further supporting its anti-inflammatory property. Metformin inhibited T cell-mediated immune responses including Ag-specific recall responses and production of Th1 or Th17 cytokines, while it induced the generation of IL-10 in spleen cells of treated EAE animals. Altogether these findings reveal that metformin may have a possible therapeutic value for the treatment of multiple sclerosis and other inflammatory diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This investigation was supported by grants (RG 3810-A-1 and PP1283) from the National Multiple Sclerosis Society (to S.G.). This work was also supported by the Extramural Research Facilities Program of the National Center for Research Resources (Grants C06 RR018823 and No C06 RR015455).

² Address correspondence and reprint requests to Dr. Shailendra Giri, Department of Experimental Pathology, Stabile 2-47, 200 First Street SW, Mayo Clinic, Rochester, MN 55905. E-mail address: giri.shailendra{at}mayo.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; PLP, proteolipid protein peptide; AMPK, AMP-activated protein kinase; iNOS, inducible NO synthase; Cox2, cyclooxygenase 2; MMP9, matrix metalloproteinase 9; ACC, acetyl CoA carboxylase; CAM, cell adhesion molecule; FFA, fatty free acid; AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; RORt, retinoid-related orphan receptor-gamma.